Structure-activity studies on phosphonoacetate

Abstract

Phosphonoacetic acid is a selective antiherpesvirus agent. More than 100 congeners of phosphonoacetic acid were evaluated in vitro and in vivo to understand structure-activity relationships in the hope of designing a superior analog. Results showed that the antiherpesvirus activity had highly specific structural requirements. Neither the carboxylic nor the phosphono groups could be replaced. The distance between these two groups is important. Increase of this distance caused complete loss of activity. However, if this distance was maintained, the addition of groups to the methylene carbon resulted in a reduction, but not loss, of activity. On the other hand, decrease of the carbon chain to formic acid did not deteriorate its antiherpes activity. All analogs tested had lower activity than the parent compound. However, some compounds with decreased activity in vitro appeared to have favorable pharmacological properties in vivo.

Increased efficacy of phosphonoformate and phosphonoacetate inhibition of herpes simplex virus type 2 replication by encapsulation in liposomes

“…1) (12, 13). For the nonencapsulated compounds, the EC50s for both PA (60 ± 25 ,uM) and PF (210 ± 85 ,uM) were consistent with previously published values (PA = 60 to 100 ,uM and PF = 60 to 200 ,uM) against various strains of HSV (8,14,15,20,22,23,24). Thus, the increase in efficacy of the liposome-encapsulated compounds (PA = 0.4 p.M, PF = 7 ,uM) could be important for in vivo antiviral activity of PA and PF.…”

“…The pKaS of the three titratable groups of PF are 7.3, 3.4, and 0.5 (34), while the analogous values for PA are 8.2, 5.0, and 2.6 (20). The poor penetration can be attributed to the multianionic nature of the phosphono compounds at physiological pH.…”

“…The poor penetration can be attributed to the multianionic nature of the phosphono compounds at physiological pH. Attempts to enhance their transport properties by chemical modifications have failed to produce more active analogs, even though a large number of congeners have been synthesized and tested (8,15,20).…”

Chemotherapeutics

“…This result prevented clinical studies from being performed with PAA. Structureactivity studies have been reported for 100 analogues of PAA, but all analogues were less active than PAA [300].…”

Inhibitors of Viral Nucleic Acid Polymerases

“…, although excep tions have been reported (16.17). Prior studies of PAA-like com pounds (15)(16)(17)(18)(19)(20) provide evidence that one phosphonate group, in close proximity (preferably one or zero intervening atoms) to a carboxylate, is associated with activity. Replacement of the carboxylate group in 2a by a phosphonate group (methanediphosphonic acid/methylene bis [phosphonic acid], MDP, 3a) resulted in loss of activity (18) .…”